1. Field of the Invention
The chemical processes of the present invention produce antibacterial agents of the class commonly called cephalosporins or intermediates for said production.
2. Description of the Prior Art
The patent literature alone contains a large number of disclosures of the production of cephalosporins by the reaction with a silylated nucleus [such as 7-aminocephalosporanic acid (7-ACA) or 7-aminodesacetoxycephalosporanic acid] of a sidechain acid in the form of its acid chloride. When that acid contains a free amino group such group is preferably blocked, as by protonation, and so use is made, for example, of 2-phenylglycylchloride hydrochloride to make cephalexin. The 4-carboxyl group of the nucleus may be blocked by silylation or by esterification. Some examples of such patents are U.S. Pat. Nos. 3,671,449, 3,694,437, 3,741,959, 3,957,773, 3,965,098, 4,051,131 and U.K. Pat. No. 1,073,530. In many instances the 3-acetoxy group of 7-ACA has been displaced before acylation by a heterocyclic thiol, e.g. ceforanide (U.S. Pat. No. 4,100,346 and see the description of prior art therein), cefatrizine (U.S. Pat. No. 3,867,380), cefaparole (U.S. Pat. No. 3,641,021), cefazolin (U.S. Pat. Nos. 3,516,997 and 3,819,623), cefazaflur (U.S. Pat. No. 3,828,037) and the like or by other types of thiols as reviewed in U.S. Pat. No. 3,928,336.
A search of Chemical Abstracts Formula Indexes Vols. 58-87 showed that I had not been indexed. ##STR1##
Siloxycarbonylamino derivatives are indexed under silanol, carbamic acid and under N-carboxy derivatives of compounds as the trimethylsilyl ester.
However, the following papers appear of some interest:
Breederveld, H.: The interaction of dialkylaminosilanes with carbon disulphide. A novel reaction in organosilicon chemistry. Recueil, 79, 1126 (1960). PA1 2. Cragg, R. H.; Lappert, M. F.: Aminoderivatives of metals and metalloids. Part IV. Aminosilylation and aminophosphination of some unsatured substrates. J. Chem. Soc. (A), 82-85 (1966). PA1 3. Kricheldorf, H. R.: Herstellung von N-Silyloxycarbonylaminosaure-derivaten. Synthesis, 259-60 (1970) (Ger.): C.A. 73, 45820r (1970). PA1 4. Kricheldorf, H. R.: The preparation of amino acid N-carboxyanhydrides (NCAs) from N-siloxycarbonyl amino acid trimethylsilyl esters. Chem. Ber., 104, 87-91 (1971) (Ger.); C.A. 74, 54156b (1971). PA1 5. Mironov, V. F.; Kozyukov, V.P.; Kirilin, A. D., et al.: Synthesis and reactions of silyl carbamates. New method for the preparation of organic isocyanates without the use of phosgene. Zh Obshch Khim, 45, 1971-1973 (1975). PA1 A is (CH.sub.3).sub.3 Si-- or an easily cleavable ester protecting group which is preferably selected from the group consisting of benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, pivaloyloxymethyl and acetoxymethyl; 1-[(ethoxycarbonyl)oxy]ethyl; and PA1 E is hydrogen, ##STR3## or --S--Z wherein Z represents a 5- or 6-membered, and preferably a 5-membered, aromatic heterocyclic ring containing two, three or four atoms of N and zero or one atom selected from the group consisting of O and S, said heterocyclic ring being optionally substituted by one or two and preferably one substituent selected from the group consisting of halo, C.sub.1 -C.sub.4 alkyl and preferably methyl, C.sub.1 -C.sub.4 alkoxy, cyano, nitro, C.sub.3 -C.sub.4 cycloalkyl, C.sub.2 -C.sub.4 alkenyl, trifluoromethyl, C.sub.1 -C.sub.4 alkylthio, di(C.sub.1 -C.sub.4 alkyl)amino, phenyl, benzyl, alkoxyalkyl of up to 4 carbons, --COOSi(CH.sub.3).sub.3 and --(CH.sub.2).sub.n COOSi(CH.sub.3).sub.3 in which n is 1, 2 or 3 and preferably n is 1, said sulfur atom in --S--Z being connected to a carbon atom of said heterocyclic ring Z and said aromatic heterocyclic ring is preferably a triazole, tetrazole, oxadiazole or thiadiazole. PA1 A is (CH.sub.3).sub.3 Si-- or an easily cleavable ester protecting group; and PA1 E is hydrogen, ##STR6## or --S--Z wherein Z represents a 5- or 6-membered aromatic heterocyclic ring containing two, three or four atoms of N and zero or one atom selected from the group consisting of O and S, said heterocyclic ring being optionally substituted by one or two substituents selected from the group consisting of halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, cyano, nitro, C.sub.3 -C.sub.4 cycloalkyl, C.sub.2 -C.sub.4 alkenyl, trifluoromethyl, C.sub.1 -C.sub.4 alkylthio, di(C.sub.1 -C.sub.4 alkyl)amino, phenyl, benzyl, alkoxyalkyl of up to 4 carbons, --COOSi(CH.sub.3).sub.3 and --(CH.sub.2).sub.n COOSi(CH.sub.3).sub.3 in which n is 1, 2 or 3, said sulfur --(CH.sub.2).sub.n COOSi(CH.sub.3).sub.3 in which n is 1, 2 or 3, said sulfur atom in --S--Z being connected to a carbon atom of said heterocyclic ring Z which comprises adding dry carbon dioxide to a solution of a compound having the formula ##STR7## wherein B is chloro, methoxy or --CH.sub.2 E; PA1 A is (CH.sub.3).sub.3 Si-- or an easily cleavable ester protecting group which is preferably selected from the group consisting of benzhydryl, benzyl, p-nitrobenzyl, p-methoxy 5-indanyl, 3-phthalidyl, pivaloyloxymethyl and acetoxymethyl; 1-[(ethoxycarbonyl)oxy]ethyl; and PA1 E is hydrogen, ##STR8## or --S--Z wherein Z represents a 5- or 6-membered, and preferably a 5-membered, aromatic heterocyclic ring containing two, three or four atoms of N and zero or one atom selected from the group consisting of O and S, said heterocyclic ring being optionally substituted by one or two and preferably one substituent selected from the group consisting of halo, C.sub.1 -C.sub.4 alkyl and preferably methyl, C.sub.1 -C.sub.4 alkoxy, cyano, nitro, C.sub.3 -C.sub.4 cycloalkyl, C.sub.2 -C.sub.4 alkenyl, trifluoromethyl, C.sub.1 -C.sub.4 alkylthio, di(C.sub.1 -C.sub.4 alkyl)amino, phenyl, benzyl, alkoxyalkyl of up to 4 carbons, --COOSi(CH.sub.3).sub.3 and --(CH.sub.2)COOSi(CH.sub.3).sub.3 in which n is 1, 2 or 3 and preferably n is 1, said sulfur atom in --S--Z being connected to a carbon atom of said heterocyclic ring Z and said aromatic heterocyclic ring is preferably a triazole, tetrazole, oxadiazole or thiadiazole in an anhydrous inert organic solvent and preferably in methylene chloride at a temperature in the range of 0.degree. C. to 100.degree. C. and preferably in the range of 0.degree. C. to 20.degree. C. until completion of the carboxylation reaction. PA1 2. With agitation of the mixture described in step 1, add 1.5 grams of sodium bisulfite and 16 grams (0.078 moles) of 1-carboxymethyl-5-mercaptotetrazole disodium. PA1 3. With agitation continuing, bubble nitrogen through the mixture for 10 minutes. PA1 4. Maintaining agitation and nitrogen inflow, heat the slurry over a 20 minute period to 56.degree. C. During this time interval, 6.5 grams of sodium bicarbonate is added in samll increments. PA1 5. With continued agitation and nitrogen inflow, maintain the temperature of the solution at 56.degree. C. for 4 hours. The pH should remain at between 6.2-6.6. PA1 6. Cool the reaction mixture in an ice bath to 5.degree. C. PA1 7. Add 50 ml. of a 1:1 phosphoric acid/water solution to the mixture or concentrated HCl to a pH of 2.0-3.0. PA1 8. Collect the product by filtration. Wash the filter cake with 20 ml. of cold water followed by 200 ml. of cold methanol. PA1 2. The following are the results of having substituted other boron trifluoride complex salts for the boron trifluoride-diethyl ether complex salt used in the above 1: PA1 3. In the above 1, substitution of propionitrile for acetonitrile resulted in 87.8% yield. PA1 4. In the above 1, substitution of sulforan for acetonitrile resulted in 90.5%, provided that the reaction conditions were 20.degree. C., 10 hours. PA1 5. In the above 1, if 1.25 ml. of 12 N hydrochloric acid is added to the reaction solution, stirring is made for 2 hours under iced condition and the deposited crystals are filtered off, washed with two 5 ml. portions of acetone and dried, there is obtained 3.20 g. (88.0% yield) of hydrochloric acid salt of 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-.DELTA..sup.3 -cephem-4-carboxylic acid, m.p. 184-186.degree. C. dec. PA1 (i) R.sup.u C.sub.n H.sub.2n CO- where R.sup.u is aryl (carboxylic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, or a non-aromatic or mesonionic heterocyclic group, and n is an integer from 1-4. Examples of this group include phenylacetyl, substituted phenylacetyl, e.g. fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methphenylacetyl, or hydroxyphenylacetyl; N,N-bis (2-chloroethyl)aminophenyl-propionyl; thien-3- and -3-acetyl; 4-isoxazolyl and substituted 4-isoxazolyacetyl; pyridylacetyl; tetrazolylacetyl or a sydnoneacetyl group. The substituted 4-isoxazolyl group may be a 3-aryl-5-methyl isoxazol-4-yl group, the aryl group being, e.g. phenyl or halophenyl, e.g. chloro- or bromo-phenyl. An acyl group of this type is 3-o-chlorophenyl-5-methyl isoxazol-4-yl-acetyl. PA1 (ii) C.sub.n H.sub.2n+1 CO-- where n is an integer from 1-7. The alkyl group may be straight or branched, and if desired, may be interrupted by an oxygen or sulphur atom or substituted by, e.g. a cyano group. Examples of such groups include cyanoacetyl, hexanoyl, heptanoyl, octanoyl and butylthioacetyl. PA1 (iii) C.sub.n H.sub.2n-1 CO-- where n is an integer from 2-7. The group may be straight or branched and, if desired, may be interrupted by an oxygen or a sulphur atom. An example of such a group is allylthioacetyl. ##STR19## where R.sup.u has the meaning defined under (i) and in addition may be benzyl, and R.sup.v and R.sup.w which may be the same or different each represent hydrogen, phenyl, benzyl, phenethyl or lower alkyl. Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-methyl-2-phenxypropionyl, p-cresoxyacetyl and p-methylthiophenoxyacetyl. ##STR20## where R.sup.u has the meaning defined under (i) and, in addition, may be benzyl and R.sup.v and R.sup.w have the meanings defined under (iv). Examples of such groups include S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl, and S-benzylthioacetyl. PA1 (vi) R.sup.u Z(CH.sub.2).sub.m CO-- where R.sup.u has the meaning defined under (i) and, in addition, may be benzyl, Z is an oxygen or sulphur atom and m is an integer from 2-5. An example of such a group is S-benzylthiopropionyl. PA1 (vii) R.sup.u CO-- where R.sup.u has the meaning defined under (i). Examples of such groups include benzoyl, substituted benzoyl (e.g. aminobenzoyl), 4-isoxazolyl- and substituted 4-isoxazolyl carbonyl, cyclopentanecarbonyl, sydone carbonyl, naphthoyl and substituted naphthoyl (e.g. 2-ethoxynapthoyl) quinoxalinylcarbonyl and substituted quinoxalinylcarbonyl (e.g. 3-carboxy-2-quinoxalinylcarbonyl). Other possible substituents for benzoyl include alkyl, alkoxy, phenyl or phenyl substituted with carboxy, alkylamido, cycloalkylamido, allylamido, phenyl(lower)alkylamido, morpholinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahydropyridino, furfurylamido or N-alkyl-N-anilino, or derivatives thereof, and such substituents may be in the 2- or 2- and 6-positions. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. Where the group R.sup.u represents a substituted 4-isoxazolyl group, the substituents may be as set out above under (i). Examples of such 4-isoxazol groups are 3-phenyl-5-methylisoxazol-4-yl carbonyl, 3-o-chlorophenyl-5-methyl isoxazol-4-yl carbonyl and 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl carbonyl. ##STR21## where R.sup.u has the meaning defined under (i) and X is amino, substituted amino (e.g. acylamido or a group obtained by reacting the amino group and/or group(s) of the 7-sidechain with an aldehyde or ketone, e.g. acetone, methylethylketone or ethyl acetoacetate), hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogeno, acyloxy, (e.g. formyloxy or lower alkanoyloxy) or etherified hydroxy group. Examples of such acyl groups are .alpha.-aminophenylacetyl, .alpha.-carboxyphenylacetyl and 2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl. ##STR22## where R.sup.x, R.sup.y and R.sup.z which may be the same or different may each represent lower alkyl, phenyl or substituted phenyl. An example of such an acyl group is triphenylcarbonyl. ##STR23## where R.sup.u has the meaning defined under (i) and in addition may be hydrogen, lower alkyl or halogen substituted lower alkyl, and Y represents oxygen or sulphur. An example of such a group is Cl(CH.sub.2).sub.2 NHCO. ##STR24## where X has the meaning defined under (viii) above and n is an integer of from 1 to 4. An example of such an acyl group is 1-amino-cyclohexanecarbonyl. PA1 (xii) Amino acyl, for example R.sup.w CH(NH.sub.2). (CH.sub.2).sub.n CO where n is an integer from 1-10, or NH.sub.2. C.sub.n H.sub.2n Ar(CH.sub.2).sub.m CO, where m is zero or an integer from 1-10, and n is 0, 1 or 2, R.sup.w is a hydrogen atom or an alkyl, aralkyl or carboxy group or a group as defined under R.sup.u above, and Ar is an arylene group, e.g. p-phenylene or 1,4-naphthylene. Examples of such groups are disclosed in British patent specification No. 1,054,806. A group of this type is the p-aminophenylacetyl group. Other acyl groups of this type include those, e.g. .delta.-aminoadipoyl derived from naturally occurring amino acids and derivatives thereof, e.g. N-benzoyl-.delta. aminoadipoyl. PA1 (xiii) Substituted glyoxylyl groups of the formula R.sup.y.CO.CO-- where R.sup.y is an aliphatic, araliphatic or aromatic group, e.g. a thienyl group, a phenyl group, or a mono-, di- or tri-substituted phenyl group, the substituents being, for example, one or more halogen atoms (F, Cl, Br, or I), methoxy groups, methyl groups, or amino groups, or a fused benzene ring. PA1 A is (CH.sub.3).sub.3 Si-- or an easily cleavable ester protecting group; and PA1 E is hydrogen, ##STR27## or --S--Z wherein Z represents a 5- or 6-membered aromatic heterocyclic ring containing two, three or four atoms of N and zero or one atom selected from the group consisting of O and S, said heterocyclic ring being optionally substituted by one or two substituents selected from the group consisting of halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, cyano, nitro, C.sub.3 -C.sub.4 cycloalkyl, C.sub.2 -C.sub.4 alkenyl, trifluoromethyl, C.sub.1 -C.sub.4 alkylthio, di(C.sub.1 -C.sub.4 akyl)amino, phenyl, benzyl, alkoxyalkyl of up to 4 carbons, --COOSi(CH.sub.3).sub.3 and --(CH.sub.2).sub.n COOSi(CH.sub.3).sub.3 in which n is 1, 2 or 3, said sulfur atom in --S--Z being connected to a carbon atom of said heterocyclic ring Z include the following:
6. Sheludyakov, V. D.; Kirilin, A. D.; Mironov, V. F.: New method for the preparation of (carbamoyloxy) silanes. Zh Obshch Khim, 45, 471 (1975).
7. Mironov, V. F.; Sheludyakov, V. D.; Kirilin, A. D.: Siloxycarbonylation of amines. Zh Obshch Khim, 46, 2297-98 (1976).
8. Farbenfabriken Bayer A-G (Oertel, G., et al.): Organosilicon compounds. Chem. Abs., 60, 6868b. (Ger. Offen. 1,157,226).